Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-Osaka, 577-8502, Japan.

2

Department of Food Science and Nutrition, Kinki University School of Agriculture, Nara, 631-8505, Japan.

3

Department of Surgery, Kinki University School of Medicine, Osakasayama, 589-8511, Japan.

4

Department of Pathology, Kinki University School of Medicine, Osakasayama, 589-8511, Japan.

5

Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-Osaka, 577-8502, Japan. nishida@phar.kindai.ac.jp.

Abstract

Interaction between multiple myeloma (MM) cells and the bone marrow microenvironment plays a critical role in MM pathogenesis and the development of drug resistance. Recently, it has been reported that MM cells express the receptor activator of nuclear factor-κB (NF-κB) (RANK). However, the role of the RANK/RANK ligand (RANKL) system in drug resistance remains unclear. In this study, we demonstrated a novel function of the RANK/RANKL system in promoting drug resistance in MM. We found that RANKL treatment induced drug resistance in RANK-expressing but not RANK-negative cell lines. RANKL stimulation of RANK-expressing cells increased multidrug resistance protein 1 (MDR1), breast cancer resistance protein (BCRP), and lung resistance protein 1 (LRP1) expression and decreased Bim expression through various signaling molecules. RNA silencing of Bim expression induced drug resistance, but the RANKL-mediated drug resistance could not be overcome through the RNA silencing of MDR1, BCRP, and LRP1 expression. These results indicate that the RANK/RANKL system induces chemoresistance through the activation of multiple signal transduction pathways and by decreasing Bim expression in RANK-positive MM cells. These findings may prove to be useful in the development of cell adhesion-mediated drug resistance inhibitors in RANK-positive MM cells.